Trastuzumab

Identification

Name
Trastuzumab
Accession Number
DB00072
Description

Produced in CHO cell cultures, trastuzumab is a recombinant IgG1 kappa, humanized monoclonal antibody 6 that selectively binds with high affinity in a cell-based assay (Kd = 5 nM) to the extracellular domain of the human epidermal growth factor receptor protein (HER2).12 It is used as a treatment of human epidermal growth factor receptor (HER)-2+ metastatic breast cancer, where there is a proven amplification of the HER-2 oncogene or over-expression of the HER-2 protein in tumours. It is suggested that the overexpression or gene amplification of HER2 has been found in about 20–30% of breast cancers and elevated activation of HER2 triggers multiple downstream pathways leading to abnormal proliferation of cancer cells 4. Trastuzumab binds to HER2 and suppresses cancer cells growth, proliferation, and survival directly and indirectly 4.

In December 2017, FDA approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). It displays biosimilar properties as Herceptin according to clinical data. While Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer, it is the second biosimilar approved in the U.S. for the treatment of cancer. Herzuma (trastuzumab-pkrb) is a biosimilar drug approved in December 2018 for the treatment of HER2-overexpressing breast cancer. KANJINTI (trastuzumab-anns) is another biosimilar approved by the FDA in June 2019.16

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Structure
Db00072
Protein Chemical Formula
C6470H10012N1726O2013S42
Protein Average Weight
145531.5 Da
Sequences
>Anti-HER2 Light chain (1 and 2)
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS
RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>Anti-HER2 Heavy chain (1 and 2)
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY
ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS
GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG
PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE
MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW
QQGNVFSCSVMHEALHNHYTQKSLSLSPGK
Download FASTA Format
Synonyms
  • RHUMAB HER2
  • trastuzumab-anns
  • trastuzumab-dkst
  • trastuzumab-dttb
  • trastuzumab-pkrb
  • trastuzumab-qyyp
External IDs
  • 4D5V8
  • ABP 980
  • ABP-980
  • DMB-3111
  • EG-12014
  • EG12014
  • R-597
  • SB-3
  • SYD-977
  • SYD977

Pharmacology

Indication

For the adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy.12

Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting.12

Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease.12

Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase15 or both hyaluronidase and pertuzumab20 - for the treatment of adults with HER-2 positive breast cancers.

Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers 7 thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo 4. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules 6. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration.12

Mechanism of action

Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers 4. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains 4. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression 4. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation 4, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation 4. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) 6 by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2 4. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC),8 one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction.9

Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor 6.

TargetActionsOrganism
AReceptor tyrosine-protein kinase erbB-2
antibody
Humans
Absorption

Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 mcg/mL.12

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

After it binds to HER2, trastuzumab is metabolized intracellularly into smaller peptides and amino acids.6

Route of elimination

Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion.6 The renal excretion of trastuzumab is very low.6

Half-life

The terminal half-life is approximately 28 days,6 but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, respectively.11

Clearance

The predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen.12 The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 L/day.15

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans.12 Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines.12

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Trastuzumab Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Receptor tyrosine-protein kinase erbB-2---(A;G)G Allele, heterozygoteADR Directly StudiedPatients with this genotype have increased risk of cardiotoxicity with trastuzumab.Details

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptTrastuzumab may increase the neutropenic activities of Abatacept.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Trastuzumab.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Trastuzumab.
AdalimumabTrastuzumab may increase the neutropenic activities of Adalimumab.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Trastuzumab.
AlclometasoneTrastuzumab may increase the neutropenic activities of Alclometasone.
AldesleukinTrastuzumab may increase the neutropenic activities of Aldesleukin.
AlefaceptTrastuzumab may increase the neutropenic activities of Alefacept.
AlemtuzumabTrastuzumab may increase the neutropenic activities of Alemtuzumab.
AlirocumabThe risk or severity of adverse effects can be increased when Trastuzumab is combined with Alirocumab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

International/Other Brands
Herclon (Roche)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
HerceptinPowder, for solution440 mgIntravenousHoffmann La Roche1999-08-23Not applicableCanada flag
HerceptinInjection, solution600 mgSubcutaneousRoche Registration Gmb H2000-08-28Not applicableEU flag
Herceptin420 mg/20mLIntravenousGenentech, Inc.1998-09-25Not applicableUS flag
HerceptinInjection, solution600 mgSubcutaneousRoche Registration Gmb H2000-08-28Not applicableEU flag
Herceptin440 mg/20mLIntravenousGenentech, Inc.1998-09-25Not applicableUS flag
HerceptinInjection, powder, for solution150 mgIntravenousRoche Registration Gmb H2000-08-28Not applicableEU flag
HerceptinInjection, powder, lyophilized, for solution150 mg/7.4mLIntravenousGenentech, Inc.2017-02-10Not applicableUS flag
Herceptin ScSolutionSubcutaneousHoffmann La Roche2018-10-12Not applicableCanada flag
HerzumaInjection, powder, lyophilized, for solution150 mg/20mLIntravenousCephalon, Inc.2020-03-16Not applicableUS flag
HerzumaKit; Powder, for solution440 mgIntravenousCelltrion2019-12-11Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Herceptin HylectaTrastuzumab (600 mg/5mL) + Hyaluronidase (human recombinant) (10000 U/5mL)Injection, solutionSubcutaneousGenentech, Inc.2019-02-28Not applicableUS flag
OgivriTrastuzumab (440 mg) + Water (20 ml)Powder, for solutionIntravenousBgp Pharma Ulc2019-06-06Not applicableCanada flag
Perjeta-herceptinTrastuzumab (440 mg) + Pertuzumab (420 mg)Kit; Powder, for solution; SolutionIntravenousHoffmann La Roche2013-05-09Not applicableCanada flag
PhesgoTrastuzumab (600 mg/10mL) + Hyaluronidase (human recombinant) (2000 U/10mL) + Pertuzumab (600 mg/10mL)Injection, solutionSubcutaneousGenentech, Inc.2020-06-29Not applicableUS flag
PhesgoTrastuzumab (600 mg/15mL) + Hyaluronidase (human recombinant) (2000 U/15mL) + Pertuzumab (1200 mg/15mL)Injection, solutionSubcutaneousGenentech, Inc.2020-06-29Not applicableUS flag

Categories

ATC Codes
L01XC03 — Trastuzumab
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
P188ANX8CK
CAS number
180288-69-1

References

General References
  1. Bange J, Zwick E, Ullrich A: Molecular targets for breast cancer therapy and prevention. Nat Med. 2001 May;7(5):548-52. [PubMed:11329054]
  2. Menard S, Pupa SM, Campiglio M, Tagliabue E: Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003 Sep 29;22(42):6570-8. [PubMed:14528282]
  3. Kute T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP: Development of Herceptin resistance in breast cancer cells. Cytometry A. 2004 Feb;57(2):86-93. [PubMed:14750129]
  4. Albanell J, Codony J, Rovira A, Mellado B, Gascon P: Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv Exp Med Biol. 2003;532:253-68. [PubMed:12908564]
  5. Tan AR, Swain SM: Ongoing adjuvant trials with trastuzumab in breast cancer. Semin Oncol. 2003 Oct;30(5 Suppl 16):54-64. [PubMed:14613027]
  6. Boekhout AH, Beijnen JH, Schellens JH: Trastuzumab. Oncologist. 2011;16(6):800-10. doi: 10.1634/theoncologist.2010-0035. Epub 2011 May 31. [PubMed:21632460]
  7. Vu T, Claret FX: Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol. 2012 Jun 18;2:62. doi: 10.3389/fonc.2012.00062. eCollection 2012. [PubMed:22720269]
  8. Rogers LM, Veeramani S, Weiner GJ: Complement in monoclonal antibody therapy of cancer. Immunol Res. 2014 Aug;59(1-3):203-10. doi: 10.1007/s12026-014-8542-z. [PubMed:24906530]
  9. Mamidi S, Cinci M, Hasmann M, Fehring V, Kirschfink M: Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab. Mol Oncol. 2013 Jun;7(3):580-94. doi: 10.1016/j.molonc.2013.02.011. Epub 2013 Feb 20. [PubMed:23474221]
  10. US Patent US6870034B2 (includes Trastuzumab heavy chain sequence) [Link]
  11. Health Canada Product Monograph: Ogivri (trastuzumab) powder for intravenous infusion [Link]
  12. FDA Approved Drug Products: Herceptin (trastuzumab) for intravenous injection [Link]
  13. FDA Approved Drug Products: Ogivri (trastuzumab-dkst) for intravenous infusion [Link]
  14. FDA Approved Drug Products: Herzuma (trastuzumab-pkrb) for intravenous infusion [Link]
  15. FDA Approved Drug Products: Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) for subcutaneous injection [Link]
  16. FDA Approved Drug Products: Kanjinti (trastuzumab-anns) for intravenous infusion [Link]
  17. FDA Approved Drug Products: Ontruzant (trastuzumab-dttb) for intravenous infusion [Link]
  18. FDA Approved Drug Products: Trazimera (trastuzumab-qyyp) for intravenous infusion [Link]
  19. Genentech: Herceptin(R) MSDS [Link]
  20. FDA News Release: FDA Approves Breast Cancer Treatment That Can Be Administered At Home By Health Care Professional [Link]
  21. FDA Approved Drug Products: Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) for subcutaneous injection [Link]
  22. Trastuzumab: Antineoplastic agent; a recombinant DNA- derived humanized anti-HER2 monoclonal antibody (complete heavy chain sequence) [File]
UniProt
P01857
Genbank
J00228
KEGG Drug
D03257
PubChem Substance
46507516
RxNav
224905
ChEMBL
CHEMBL1201585
Therapeutic Targets Database
DAP000391
PharmGKB
PA451743
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Trastuzumab
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
MSDS
Download (320 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentBreast Cancer1
4CompletedDiagnosticBreast Cancer1
4CompletedTreatmentBreast Cancer3
4TerminatedTreatmentMalignant Neoplasm of Stomach1
4TerminatedTreatmentMetastatic Breast Cancer1
4Unknown StatusTreatmentHer-2 Positive Gastric Cancer / Liver Metastasis1
3Active Not RecruitingTreatmentAdenocarcinoma Of Esophagus / Adenocarcinomas of the Gastroesophageal Junction / Stage IB Esophageal Cancer AJCC v7 / Stage IIA Esophageal Cancer AJCC v7 / Stage IIB Esophageal Cancer AJCC v7 / Stage IIIA Esophageal Cancer AJCC v7 / Stage IIIB Esophageal Cancer AJCC v71
3Active Not RecruitingTreatmentBreast Cancer10
3Active Not RecruitingTreatmentBreast Cancer / HER2 Positive1
3Active Not RecruitingTreatmentBreast Cancer / HER2 Positive Breast Cancers / Neoplasms, Breast / Stage II Breast Cancer / Stage IIIA Breast Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • DSM Corp.
  • F Hoffmann-La Roche Ltd.
  • Genentech Inc.
Dosage Forms
FormRouteStrength
Injection150 mg
Injection
Injection, powder, for solution
Injection, powder, for solutionIntravenous150 mg
Injection, powder, lyophilized, for solutionIntravenous150 mg/7.4mL
Injection, solutionCutaneous600 MG/5ML
Injection, solutionCutaneous600 MG
Injection, solutionSubcutaneous600 mg
Injection, solution, concentrateIntravenous150 mg
Injection, solution, concentrateIntravenous440 mg
Powder, for solutionIntravenous440 mg
Solution
Injection, solutionSubcutaneous
Injection, powder, lyophilized, for solutionIntravenous150 mg
Injection, solution600 mg/5mL
SolutionSubcutaneous
Powder
Injection, powder, lyophilized, for solutionIntravenous150 mg/20mL
Kit; powder, for solutionIntravenous440 mg
Injection, powder, lyophilized, for solutionIntravenous150 mg/7.15mL
Injection, powder, lyophilized, for solutionIntravenous420 mg/20mL
Kit; powder, for solutionIntravenous420 mg
Powder, for solutionIntravenous
Powder, for solutionIntravenous150 mg
Injection, powder, lyophilized, for solutionIntravenous440 mg
Injection, powder, for solutionIntravenous; Parenteral150 MG
Injection, powder, for solutionIntravenous; Parenteral420 MG
Injection, powder, lyophilized, for solutionIntravenous150 mg/1
KitIntravenous420 mg/1
Kit; powder, for solution; solutionIntravenous
Powder, for solutionIntravenous
Injection, powder, for solutionIntravenous440 mg
Injection, powder, lyophilized, for solution
Prices
Unit descriptionCostUnit
Herceptin 440 mg Solution Vial3581.2USD vial
Herceptin 440 mg vial3443.46USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2103059No2005-03-222012-06-15Canada flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)61 °C (FAB fragment), 71 °C (whole mAb)Vermeer, A.W.P. & Norde, W., Biophys. J. 78:394-404 (2000)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antibody
General Function
Transmembrane signaling receptor activity
Specific Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, alt...
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Leveque D, Gigou L, Bergerat JP: Clinical pharmacology of trastuzumab. Curr Clin Pharmacol. 2008 Jan;3(1):51-5. [PubMed:18690878]
  3. Lin A, Rugo HS: The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. Curr Treat Options Oncol. 2007 Feb;8(1):47-60. [PubMed:17660958]
  4. Treish I, Schwartz R, Lindley C: Pharmacology and therapeutic use of trastuzumab in breast cancer. Am J Health Syst Pharm. 2000 Nov 15;57(22):2063-76; quiz 2077-9. [PubMed:11098307]

Drug created on June 13, 2005 07:24 / Updated on October 27, 2020 11:13

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